Further evidence for a maternal genetic effect and a sex-influenced effect contributing to risk for human neural tube defects.
BACKGROUND
Neural tube defects (NTDs), including spina bifida and anencephaly, are the second most common birth defect with an incidence of 1/1000. Genetic factors are believed to contribute to NTD risk and family-based studies can be useful for identifying such risk factors.


METHODS
We ascertained 1066 NTD families (1467 affected patients), including 307 multiplex NTD families. We performed pedigree analysis to describe the inheritance patterns, pregnancy outcomes, and recurrence risks to relatives of various types.


RESULTS
Myelomeningocele or spina bifida (66.9%) and cranial defects (17.7%) were the most common NTD subtypes observed. The overall male:female ratio for affected individuals was 0.82, and there were even fewer males among individuals with an upper level NTD (0.62). Among twins, 2 of the 5 monozygotic twins and only 3 of 35 dizygotic twins were concordant, while 27% of the same sex twins were concordant, but none of the different sex twins. The estimated 6.3% recurrence risk to siblings (CI 0.04-0.08) is consistent with previous reports. Families with two or more affected individuals show a higher proportion of female transmitters (p = 0.0002). Additionally, the number of affected relatives in maternal compared to paternal lineages was more than double (p = 0.006). There were significantly more miscarriages, infant deaths, and stillborn pregnancies of the maternal aunts and uncles (p < 0.0001) and of first cousins (p = 0.04).


CONCLUSIONS
Our data provide several lines of evidence consistent with a maternal effect, as well as a sex-influenced effect, in the etiology of NTDs.
Deak
Kristen L
KL
Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Siegel
Deborah G
DG
George
Timothy M
TM
Gregory
Simon
S
Ashley-Koch
Allison
A
Speer
Marcy C
MC
D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D009035:Mothers; D009436:Neural Tube Defects / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D011256:Pregnancy Outcome; D012307:Risk Factors; D012737:Sex Factors; D014427:Twins